MACE and Hyperthyroidism Treated With Medication, Radioactive Iodine, or Thyroidectomy

This cohort study investigates the association of antithyroid drug, radioactive iodine, and surgery treatments with major adverse cardiovascular events in patients with newly diagnosed hypothyroidism.


eNote 2: A brief introduction to landmark analysis and our study design
The landmark analysis involves the use of a predetermined landmark time during follow-up to assess subjects who have survived up to that designated point. 1 In studies where there is a delay or waiting period to ascertain a subject's treatment status, immortal time may occur. 2 Therefore, for studies susceptible to immortal time bias, landmark analysis can help prevent such bias by excluding subjects who died or became ineligible before the landmark time. 1 Subjects are then categorized according to their status at the landmark time and the outcome of interest is followed afterwards.
eFigure 1 visually represented our study design.The landmark, which was also the index date, was set at 18 months after diagnosis.Primary outcomes of MACE and all-cause mortality were followed from the index date.
Between the date of diagnosis and the index date was the period of treatment assignment.During this timeframe, the timing of when patients initiated each treatment could vary.Those who exclusively received ATD treatment were categorized into the ATD group.Patients in the RAI group and surgery group could receive antithyroid drug before their respective treatments.e In accordance with the data privacy protection regulation of the Ministry of Health and Welfare's Statistics Department, specific numbers cannot be disclosed when there are fewer than 3 events.However, the event number presented is calculated using inverse probability of treatment weighting, reflecting a weighted figure rather than the exact count of events

eFigure 2 .
The crude cumulative incidence curves of ATD, RAI, and surgery for (A) MACE and (B) all-cause mortality without IPTW MACE, major adverse cardiovascular events; ATD, anti-thyroid drug; RAI, radioactive iodine

Baseline characteristics and comorbidities of patients with hyperthyroidism analyzed for MACE composite outcome before IPTW
© 2024 Peng CCH et al.JAMA Network Open.

Baseline characteristics and comorbidities of patients with hyperthyroidism analyzed for all-cause mortality after IPTW a
© 2024 Peng CCH et al.JAMA Network Open.ATD, anti-thyroid drug; RAI, radioactive iodine; IPTW, inverse probability of treatment weighting; SMD, standardized mean difference; NOAC, Non-Vitamin K antagonist oral anticoagulants; ARB, Angiotensin II receptor blockers; ACEi, Angiotensin-converting enzyme inhibitors; GLP1-RA, Glucagon-like peptide-1 receptor agonists; SGLT2i, Sodium-glucose cotransporter-2 inhibitors a A pseudopopulation constructed by stabilized IPTW for analyses.bAstandardizedmeandifference of < 0.1 indicates a negligible difference.cInaccordancewith the data privacy protection regulation of the Ministry of Health and Welfare's Statistics Department, specific numbers cannot be disclosed when there are fewer than 3 events.However, the event number presented is calculated using inverse probability of treatment weighting, reflecting a weighted figure rather than the exact count of events.©2024 Peng CCH et al.JAMA Network Open.eTable 9.

Risks of MACE and all-cause mortality stratified by age among patients with hyperthyroidism treated with ATD, RAI or surgery after IPTW a
© 2024 Peng CCH et al.JAMA Network Open.© 2024 Peng CCH et al.JAMA Network Open.MACE, major adverse cardiovascular events; ATD, anti-thyroid drug; RAI, radioactive iodine; IPTW, inverse probability of treatment weighting; NA, not applicable a A pseudopopulation constructed by stabilized IPTW for analyses.bIneach outcome analysis, patients who had already experienced the corresponding outcome event before the index date were excluded.eTable 10.

Risks of MACE and all-cause mortality stratified by sex among patients with hyperthyroidism treated with ATD, RAI or surgery after IPTW a
© 2024 Peng CCH et al.JAMA Network Open.© 2024 Peng CCH et al.JAMA Network Open.MACE, major adverse cardiovascular events; ATD, anti-thyroid drug; RAI, radioactive iodine; IPTW, inverse probability of treatment weighting a A pseudopopulation constructed by stabilized IPTW for analysesbIn each outcome analysis, patients who had already experienced the corresponding outcome event before the index date were excluded.

Table 11 . Risks of MACE and all-cause mortality stratified by healthcare utilization among patients with hyperthyroidism treated with ATD, RAI or surgery after IPTW a
Healthcare utilization was determined based on the number of clinic visits in the year preceding the index date.The lower group comprised patients with clinic visit numbers in the bottom 50%, while the higher group included those in the top 50%.Median[IQR] clinic visits for overall MACE, AMI, stroke, heart failure, cardiovascular mortality: ATD group 15 [15], RAI group 18 [16], surgery group 19 [17] Median [IQR] clinic visits for all-cause mortality: ATD group 15 [16], RAI group 19 [17], surgery group 20 [19] © 2024 Peng CCH et al.JAMA Network Open.© 2024 Peng CCH et al.JAMA Network Open.MACE, major adverse cardiovascular events; ATD, anti-thyroid drug; RAI, radioactive iodine; IPTW, inverse probability of treatment weighting; NA, not applicable a A pseudopopulation constructed by stabilized IPTW for analyses b In each outcome analysis, patients who had already experienced the corresponding outcome event before the index date were excluded.© 2024 Peng CCH et al.JAMA Network Open.c Per 100,000 person-years d

Risks of MACE and all-cause mortality stratified by index year among patients with hyperthyroidism treated with ATD, RAI or surgery after IPTW a
In each outcome analysis, patients who had already experienced the corresponding outcome event before the index date were excluded.Per 100,000 person-years d In accordance with the data privacy protection regulation of the Ministry of Health and Welfare's Statistics Department, specific numbers cannot be disclosed when there are fewer than 3 events.However, the event number presented is calculated using inverse probability of treatment weighting, reflecting a weighted figure rather than the exact count of events © 2024 Peng CCH et al.JAMA Network Open.

Risks of hyperthyroidism relapse stratified by age among patients with hyperthyroidism treated with ATD, RAI or surgery after IPTW a
ATD, anti-thyroid drug; RAI, radioactive iodine; IPTW, inverse probability of treatment weighting; OR, odds ratio; CI, confidence interval a Patients who had both RAI and surgery were included in the analysis.A pseudopopulation constructed by stabilized IPTW for analyses eTable 15.

Risks of hyperthyroidism relapse stratified by sex among patients with hyperthyroidism treated with ATD, RAI or surgery after IPTW
ATD, anti-thyroid drug; RAI, radioactive iodine; IPTW, inverse probability of treatment weighting; OR, odds ratio; CI, confidence interval a Patients who had both RAI and surgery were included in the analysis.A pseudopopulation constructed by stabilized IPTW for analyses © 2024 Peng CCH et al.JAMA Network Open.eTable 16.

Sensitivity Analysis: Risks of MACE and all-cause mortality in hyperthyroid patients treated with ATD, RAI, or surgery, with landmark time (index date) at 24 months post-diagnosis after IPTW a
MACE, major adverse cardiovascular events; ATD, anti-thyroid drug; RAI, radioactive iodine; IPTW, inverse probability of treatment weighting a A pseudopopulation constructed by stabilized IPTW for analysesbIn each outcome analysis, patients who had already experienced the corresponding outcome event before the index date were excluded.c Per 100,000 person-years eTable 17.

Sensitivity analysis after excluding incidental thyroid cancer a : Risks of MACE and all-cause mortality in patients with hyperthyroidism treated with ATD, RAI, or surgery after IPTW
, major adverse cardiovascular events; ATD, anti-thyroid drug; RAI, radioactive iodine; IPTW, inverse probability of treatment weighting; HR, hazard ratio; CI, confidence interval a Incidental thyroid cancer was diagnosed during observation period.In each outcome analysis, patients who had already experienced the corresponding outcome event before the index date were excluded.In accordance with the data privacy protection regulation of the Ministry of Health and Welfare's Statistics Department, specific numbers cannot be disclosed when there are fewer than 3 events.However, the event number presented is calculated using inverse probability of treatment weighting, reflecting a weighted figure rather than the exact count of events © 2024 Peng CCH et al.JAMA Network Open.
© 2024 Peng CCH et al.JAMA Network Open.MACEb c Per 100,000 person-years d

eTable 18. Sensitivity analysis using propensity score matching: Risks of MACE and all- cause mortality in patients with hyperthyroidism treated with ATD, RAI, or surgery
, major adverse cardiovascular events; ATD, anti-thyroid drug; RAI, radioactive iodine; IPTW, inverse probability of treatment weighting; HR, hazard ratio; CI, confidence interval a In each outcome analysis, patients who had already experienced the corresponding outcome event before the index date were excluded.